Graft-versus-host-disease (GVHD) is a life threatening complication of hematopoietic stem cell transfer (HSCT) and is the major factor in failure of HSCT. Current treatment of GVHD most commonly involves the use of immunosuppressive drugs and hence places the recipient in an immunocompromised state. Strategies that allow HSCT without the complication of GVHD would open the possibility of broader use of HSCT in the treatment of several hematologic malignancies. The major obstacle for routine use of HSCT is the profound complications that can occur from GVHD. It is well known that GVHD is mediated by activated T cells therefore an early approach was to completely delete T cells from the donor cell population prior to transfer. While this approach eliminated GVHD, it also profoundly inhibited effective engraftment as well as development of the therapeutic graft-versus-leukemia (GVL) response. Therefore current protocols include T cells in the donor cell population. This results in a high incidence of GVHD in adults receiving HSCT. Our preliminary data, presented in this application, supports a role for substrates of y-secretase in GVHD. Our data clearly demonstrate that substrates of y-secretase play an important role in GVHD and treatment of recipients with GSI inhibits GVHD. We also show that GVHD is accompanied by activation of Notch1 in donor T cells, suggesting that an important target of GSI in GVHD is Notch1. Lastly our studies with Notch deficient T cells firmly establish that Notch is one relevant target of GSI in these experiments. The experiments in this project are designed to test the hypothesis that y-secretase inhibitors may have significant clinical utility in the treatment of GVHD while maintaining graft-versus-leukemia (GVL). We then propose a series of experiments to determine the mechanisms by which y-secretase inhibitors function to block GVHD and suggest that such an understanding may lead to rational mechanistic based approach to the treatment of GVHD.